Treatment of Rabbit Rotator Cuff Fatty Infiltration and Atrophy with Electric Stimulation and a PDGFRa inhibitor

电刺激和 PDGFRa 抑制剂治疗兔肩袖脂肪浸润和萎缩

• 批准号: 10641248
• 负责人: Mohit Gilotra
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2028-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641248
• 关键词: Acute; Adipocytes; Affect; Alpha Cell; Animal Model; Animals; Atrophic; Award; Biology; Biopsy; Cells; Chronic; Clinical; Clinical Trials; Data; Diagnosis; Disuse Atrophy; Electric Stimulation; Euthanasia; Exhibits; FDA approved; Fatigue; Fatty acid glycerol esters; Fibrosis; Frequencies; Future; Gait; Goals; Healthcare Systems; Histology; Human; Hyperplasia; Image; Imaging Techniques; Immobilization; Incidence; Infiltration; Injury; Intervention; Lead; Maryland; Measures; Mechanics; Mesenchymal; Methods; Modeling; Mus; Muscle; Muscle function; Muscular Atrophy; Natural regeneration; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Outcome; Outcome Measure; Outcome Study; PDGFA gene; Patients; Pattern; Pharmaceutical Preparations; Physiologic pulse; Physiological; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor alpha Receptor; Prevention; Probability; Prognostic Factor; Property; Receptor Inhibition; Recovery; Rehabilitation therapy; Reproducibility; Research; Research Design; Research Methodology; Research Personnel; Research Support; Rotator Cuff; Scientist; Shoulder; Surgeon; Tendon structure; Testing; Tetany; Time; Tissues; United States Department of Veterans Affairs; Veterans; Work; X-Ray Computed Tomography; adipocyte biology; antagonist; career; disability; experience; functional improvement; functional outcomes; gait examination; healing; improved; improved outcome; in vivo; in vivo Model; inhibitor; microCT; military veteran; mouse model; muscle physiology; muscle regeneration; non-invasive imaging; novel; pain reduction; pharmacologic; pre-clinical; preservation; prevent; programs; rehabilitation research; repair model; repaired; research and development; rotator cuff injury; rotator cuff tear; supraspinatus muscle; translational research program; viscoelasticity

Background: The PI proposes to test the hypothesis that inhibition of platelet-derived growth factor receptor alpha (PDGFRa) and direct, submaximal electric stimulation (ES) synergistically prevents fatty infiltration (FI) and muscle atrophy, improving function after rotator cuff tear. A large irreparable rotator cuff tear with muscle FI is one of the most common diagnoses seen in his VA practice. According to the Veterans Administration Surgical Quality Improvement Program, over 10,000 Veterans with rotator cuff injuries underwent rotator cuff repairs over a six-year span. Surgical repair of a torn rotator cuff is generally successful, though with a re-tear rate of 25 percent. We propose a novel method of FI prevention and will study how this affects muscle function. Fatty infiltration and atrophy leads to poor outcomes from tendon re-tear and decreased muscle function. Objectives: The overall purpose of this proposal is to determine whether the treatment of FI and atrophy improves outcomes in a rabbit animal model such as: animal gait, muscle function, and rotator cuff healing.  Aim 1: Determine if PDGFR inhibition and direct muscle ES at the time of rotator cuff tear can improve muscle function by preventing FI and atrophy in an established rabbit rotator cuff tear model.  Aim 2: Determine if PDGFR inhibition and direct muscle ES can arrest/impede FI and improve function using a delayed repair model in which FI and atrophy have been established. Research Design and Methodology: This study will utilize an established and reproducible rabbit in vivo model of chronic rotator cuff tear and muscle fatty infiltration in Aims 1 and 2. Study outcome measures for both aims include: in vivo contractile muscle function testing, rabbit gait analysis, quantitative-based micro-CT imaging of muscle fatty infiltration, tissue analysis for fibro-adipogenic cells and fat/fibrosis specific histology. Specific Aim 2 will utilize these same outcomes, as well as tendon functional testing to determine viscoelastic properties. Clinical Relationships: Rotator cuff tear with irreversible FI is common in the Veteran population and precludes a successful repair and outcome. The ultimate goal is finding novel interventions that can improve function for Veterans undergoing rotator cuff repair. Impact/Significance: The proposed Merit Award will lay the groundwork for future clinical trials within the next ten years by testing two Federal Drug Agency approved treatments for their synergistic effects on the treatment of atrophic rotator cuff tears. This translational pre-clinical approach has the potential to: reduce pain and improve Veteran's ability to function independently and return to physical work. Furthermore, it will provide valuable research support for the applicant as he pursues a career as an orthopaedic surgeon-scientist at the VA Maryland Health Care System. [The PI has a team of three co-investigators experienced in rotator cuff imaging, rotator cuff muscle physiology and adipocyte formation.]

背景：本实验旨在验证血小板源性生长因子的抑制假说